Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.


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Reporting for specific materials, systems and methods The AGES-RS proteomics study included all 5457 individuals from the single-center prospective population-based AGES-RS study for whom protein measurements were available as well as comprehensive genotype and phenotype information.
For the animal studies (Fig. 1-2-3-4-6) sample sizes were not calculated prior to performing experiments.All the in vivo metabolic phenotyping work, included largely => n = 6/group).Importantly, in many instances, paired comparisons (before and after intervention, In vitro work using cell lines was repeated in 3 independent experiments. Individuals with missing genotype, phenotype information and protein measurements were excluded from the study.Extreme proteomic outliers were excluded (>4.3 SD) prior to statistical analysis.
In the mouse energy expenditure data -as reported in the Source file Fig. 1, Fig. 6-data points excluded (highlighted in blue in the excel file) if for example a cage was opened due to sampling that would have affected monitoring of energy expenditure.This was done across groups so no data bias.
For the animal studies, the core metabolic phenotyping in both sexes described in FIG1-2-3 was replicated in 2 independent experiments (replication was successful) experiments using cell line replicated in 3 independent experiments The participants in the AGES-RS study were not randomized into experimental groups.More to the point, AGES-RS is a population-based study of survivors from the 40-year-long prospective Reykjavik study (random sample of 30,795 individuals), an epidemiologic study aimed at understanding aging in the context of gene/environment interactions by focusing on four biologic systems: vascular, neurocognitive (including sensory), musculoskeletal, and body composition/metabolism.Animal experiments: For animal experiments, mice were randomly allocated to treatment groups.In vitro, individual wells were randomly assigned different drug treatments Blinding for the human AGES-RS proteomics study was not relevant as this study did not compare experimental groups.For all animal experiments described in the manuscript mice, the operator was blind to the genotype.Blinding maintained throughout in vivo and in vitro experiments.
agreement with the IHA.All access to data is controlled via the use of a subject-signed informed consent authorization.The time it takes to respond to requests varies depending on their nature and circumstances of the request, but it will not exceed 14 working days.Summary statistics data for each protein's genetic determinants, i.e., protein quantitative trait loci (QTLs), have been released to a public repository (GWAS catalogue), with accession numbers detailed in Gudjonsson et al. (PMID: 35078996).Mass spectrometry data (DDA or MRM) were deposited to the ProteomeXchange Consortium with the dataset identifiers PXD008819 to PXD008823, as well as the dataset identifier PASS01145, to determine the specificity of aptamers binding to target proteins (PMID: 30072576).The RNA-sequencing raw data have been uploaded to NCBIs' Gene Expression Omnibus (GEO) database and can be downloaded with GEO accession number GSE269003.Source data are provided with this paper.